This renewal program project proposal seeks support for studies searching for the cellular and molecular mechanisms in models of human neuropathy and particularily in human diabetic neuropathy itself. Project 1, is a cross-sectional and longitudinal epidemiologic study of all insulin-dependent (ID, 80) and a representative sample of non insulin-dependent (NID, 525) diabetics in Rochester, MN, designed to provide reliable estimates of the frequency, severity and outlook of neuropathic, retinal and renal complications, using validated and often unique tests. Metabolic derangement and putative risk factors are prospectively and intensively evaluated so that associations with end-points of neuropathy can be recognized. Project 2, proposes a series of neuropathologic studies of nerve tissue obtained at postmortem, and of sural nerve taken at biopsy, addressing the fundamental question are pathologic abnormalities of vessels and ischemia involved in the pathogenesis of diabetic neuropathy. Which class of vessels, what pathologic alterations, and what mechanisms are responsible? The association of metabolic derangement and putative risk factors, as assessed in Projects 1 and 2, and quantitated neuropathologic abnormality, are to be assessed. An intensive search for microinfarcts is to be conducted. Arteriole-capillary-venule (ACV) units are to be reconstructed from serial sections to understand the pattern of microvascularization in health and diabetic neuropathy. Hypoxia, arterial ligation, microsphere embolization, nerve degeneration, lead intoxication and experimental diabetes in rats are used to induce vessel and nerve fiber alterations with the view to understanding the relationship between vessel and fiber abnormality in human neuropathy. Project 3 extends previous studies of alterations of the nerve microenvironment in experimental diabetes to chronic autoimmune diabetic neuropathy and to human diabetic neuropathy. The hierarchy of nerve blood flow regulation, the mechanisms of capillary closure in hypoxia and pharmacologic and hyperbaric oxygen approaches to increase nerve blood flow will be studied. Mathematical modeling and computer simulation of oxygen delivery and events of energy metabolism will also be studied. Project 4 focuses on the study of alteration of the blood-nerve-barrier in experimental and human neuropathies, emphasizing diabetic neuropathy. Project 5 outlines studies to isolate and characterize the soluble neuronatrophic factor produced in response to injury. The studies address which cells produce the trophic factor, and the biologic role of this factor in development and regeneration of nerve fibers in health and disease. Project 6 continues biochemical studies to illucidate derangements of phospholipid metabolism in peripheral neuropathy and especially in diabetic neuropathy. Biosynthetic and degradative enzymes of phospholipid metabolism will be characterized. The effect of altering inositol phospholipid metabolism with lithium will also be studied.